Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.
Considerable interest exists in the development of pharmaceutical formulations which are capable of selective delivery of drugs into the colon and other sites within the gastrointestinal tract. Site specific delivery to the colon provides certain advantages for the development of pharmaceutical products. Delivery of therapeutic agents specifically to the colon allows treatment of diseases and disorders that primarily affect the colon. Colonic disorders which may benefit from selective delivery of drug include, but are not limited to, intestinal bowel diseases such as Crohn's disease and ulcerative colitis, irritable bowel syndrome, spastic colon, C. difficile infection, constipation and colon cancer.
The ability to deliver such compounds to the gastrointestinal tract using an orally administered formulation provides for more convenient administration and better patient compliance. Furthermore, localized delivery of therapeutic agents to the gastrointestinal tract via the oral route may lead to improved efficacy of the agent while reducing the side effects associated with parenteral administration of such a compound. The colon is often identified as a preferred delivery site because of slow transit, its small volume and a lack of vigorous stirring within it, leading to an ability to create local conditions favorable to stabilization of the drug. The colon also lacks certain digestive enzymes (proteases) that can affect adversely drug stability.
Several approaches for site-specific delivery to the gastrointestinal tract have been employed including time release, pH-responsive or microbial-trigger approaches. Delivery systems that use time-based release mechanisms take into consideration the typical gastrointestinal transit time in humans, and seek to release of the drug in the small and large intestine. Microbial trigger drug delivery systems take advantage of the colonic microbiota to digest polymer coatings in the colon while resisting digestion in the small intestine. Delivery systems based on a pH responsive mechanism are designed to trigger drug release based on the pH associated with different regions of the intestinal tract to target drug delivery at specific sites in the intestine.
Site-specific delivery into the small intestine has been achieved for many years by the use of pH-sensitive (enteric) coatings. By optimizing the formulation, in particular, the type of polymer, delivery to specific target sites with the gastrointestinal tract can be achieved. While this approach has been successful in providing enteric dosage forms for delivering small molecule therapeutic agents, use of this approach for delivering biological macromolecular therapeutic agents such as proteins has been less successful due to the sensitivity of such agents to the formulation and processing methods used to prepare such enteric formulations.
Various attempts to overcome the sensitivity problems associated with biological macromolecular therapeutic agents (e.g., proteinaceous agents) have been proposed which include initial preparation of lyophilates. For instance, U.S. Pat. No. 5,597,562 discloses pharmaceutical preparations that are stated to allow absorption of granulocyte colony stimulating factor and erythropoietin from the gastrointestinal tract. The patent discloses that the drug preparations are prepared by lyophilizing a solution containing the protein, a fatty acid, an optional excipient, in a buffer solution to form a powder. The powder is used either to fill a capsule or formed into granules, which are then enterically coated.
Similarly, U.S. Pat. Nos. 3,860,490 and 3,767,790 disclose the entrapment of influenza vaccine in hydrophilic polyacrylates or polymethacrylates to provide controlled release formulations. U.S. Pat. No. 4,397,844 discloses the formation of chemical derivatives of antigens, including derivatives of influenza vaccine, which are said to produce an increase in immunoresponse and which are formulated with solid excipients to make tablets or tablet cores. EP-A 86/06635 discloses a complex of an immunogen to interact with the mucosal ephithelium upon oral administration. Mercier, G. T et al. in Oral Immunization of Rhesus Macaques with Adenoviral HIV Vaccines Using Enteric-Coated Capsules, Vaccine 25, pp 8687-8701 (2007) discloses enterically coated hydroxypropylmethyl cellulose capsules containing lyophilized adenoviral vectors.
Several drawbacks are associated with use of conventional lyophilized bulk powder approach which are filled into capsules or compressed into tablets that are enterically coated for targeting the unitary dosage form (capsule/tablet) to the intestinal tract. The lyophilized bulk powder is often fluffy and is associated with poor bulk density that results in inadequate powder flow. In order to improve the powder flow, the lyophilized bulk is often blended with flow enhancers such as glidants along with other commonly used pharmaceutical excipients such as lubricants, disintegrants, and fillers. If the powder blend fails to have adequate flow properties, then inconsistent loading of the dose during subsequent downstream processing such as capsule filling or tablet compression will result in poor dose uniformity in the final dosage form. Furthermore, macromolecules such as proteins destabilize more readily compared to small molecules during blending with excipients due to chemical instability with the excipients. In addition, the macromolecule is subject to degradation due to the physical stress induced on the macromolecule during tablet compression processes or in the tamping processes used to fill capsules.
Furthermore, in the process of enterically coating the capsules, softening of the gelatin shell may occur during the coating step. The polymeric film may also insufficiently adhere to the capsule during the coating step, in particular, when using coating with organic solvents, resulting in peeling and splintering of the capsule. Other drawbacks resulting from the coating step include powder leakage from capsule caused by separation of the capsule body and cap. Insufficient capsule integrity may also result in cracking of the polymeric film during the drying step of the enteric coating process.
While lyophilates have been used to prepare biological materials for storage and further processing into suitable dosage forms, another technique for preparing such materials involves preparing lyospheres. U.S. Pat. No. 3,655,838 discloses a process for separate freeze-drying of the various solutions comprising the various biological materials for a diagnostic test. Briefly, this process includes bringing droplets of each solution in direct contact with liquid nitrogen resulting in instantaneous freezing. The frozen droplets are transferred to a freeze-dryer and are subsequently dried. The resulting dry spheres are called lyospheres. The first lyospheres owed their form and name to the fact that they were frozen as spherical droplets and subjected to lyophilisation afterwards. Small volumes of fluid in any possible form can also be frozen by contacting them with cold surfaces, e.g., by adding some fluid to small holes in a cold heat-conducting surface, followed by lyophilisation.
U.S. Pat. No. 9,119,794 also discloses a process for forming a lyosphere which is in the form of a tablet. Such processes are disclosed to be able to result in fast-disintegrating tablets containing a medicinal substance which are suitable for oral use.
U.S. Patent Application Publication No. US2014/0294872 discloses a process for preparing lyophilized pellets of biological materials. The pellets are said to have a substantially spherical shape, and are prepared by freezing droplets of a liquid composition of a desired biological material on a flat, solid surface, in particular, a surface that does not have any cavities, followed by lyophilizing the frozen droplets. These processes are stated to be useful for preparing lyophilized pellets having a high concentration of a desired biological material, in particular a therapeutic protein or vaccine, and which have a faster reconstitution time than lyophilized powder cakes prepared in vials.
New processes for preparing enterically-coated dosage forms that are, in particular, suitable for macromolecular therapeutic agents are desirable. New dosage forms that specifically deliver therapeutic agents to the ileum, ileo-caecal junction, colon or a combination thereof in patients provide health care practitioners with additional options to treat diseases or disorders. For instance, in the therapy of certain disorders such as an irritable bowel disease or C. difficile infection, delivering a therapeutic agent to such sections of the gastrointestinal tract is particularly desirable.
The present invention provides such processes, dosage forms and delivery methods.